Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study.

UNLABELLED: Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. INTRODUCTION: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. MATERIALS AND METHODS: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. RESULTS: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. CONCLUSIONS: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.

Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the monthly oral pilot study.

CONTEXT: Ibandronate, a potent, nitrogen-containing bisphosphonate developed for intermittent administration in postmenopausal osteoporosis, aims to overcome current adherence issues with daily and weekly oral bisphosphonates through once-monthly oral dosing. OBJECTIVE: The purpose of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of once-monthly oral ibandronate. DESIGN: A randomized, 3-month, double-blind, placebo-controlled, phase I study (Monthly Oral Pilot Study) was conducted. SETTING: The study was conducted at five clinical trial centers in the United Kingdom and Belgium. PATIENTS OR OTHER PARTICIPANTS: Subjects were postmenopausal women (age, 55-80 yr; > or =3 yr post menopause; n = 144). INTERVENTION(S): Once-monthly oral ibandronate 50, 100, or 150 mg or placebo was used. After the first cycle, the 50-mg arm was split, with participants continuing on either 50 or 100 mg. MAIN OUTCOME MEASURE(S): Primary outcome measures were safety, serum and urinary C-telopeptide (CTX), and serum ibandronate AUC0-infinity. RESULTS: Once-monthly oral ibandronate was well tolerated, with a similar overall and upper gastrointestinal safety profile to placebo. Once-monthly ibandronate was also highly effective in decreasing bone turnover; substantial reductions from baseline in serum CTX (-56.7% and -40.7% in the 150- and 100-mg arms, respectively; P < 0.001 vs. placebo) and urinary CTX (-54.1% and -34.6%, respectively; P < 0.001 vs. placebo) were observed at d 91 (30 d after the final dose). Analysis of the area under the effect curve (d 1-91) for change from baseline (percent x days) in serum CTX and urinary CTX indicated a dose-response relationship. The AUC0-infinity for ibandronate increased with dose but not in a dose-proportional manner. CONCLUSIONS: These findings indicate a potential role for once-monthly oral ibandronate in the treatment of postmenopausal osteoporosis.

Effects of intermittent intravenous ibandronate injections on bone quality and micro-architecture in women with postmenopausal osteoporosis: the DIVA study.

In the Dosing IntraVenous Administration (DIVA) study, IV ibandronate injections (15-30 s duration) provided significantly greater gains in bone mineral density than daily oral ibandronate (P<0.001). Single transiliac bone biopsy was performed in a subgroup of women (n=109/1395) from DIVA to assess the impact of ibandronate on newly formed bone and bone remodeling. Patients received ibandronate IV injections 2 mg every 2 months, 3 mg every 3 months or oral ibandronate 2.5 mg daily, plus oral or IV placebo, as appropriate to maintain blinding. Of the 1395 participants from the DIVA study, 122 were enrolled in the substudy. Qualitative histological analysis was performed on all biopsy cores and 89 cores were considered to be evaluable for quantitative histomorphometry. Following 2 years of ibandronate treatment, trabecular bone maintained its normal lamellar structure with no evidence of woven bone, marrow fibrosis, cellular toxicity, or other qualitative abnormalities. Primary mineralization of new bone remained normal, as indicated by the slightly lower osteoid thickness and osteoid volume, with normal mineral apposition rate compared to healthy, postmenopausal women. Mineralizing surface, osteoid surface, activation frequency and bone formation rate were decreased in all ibandronate-treated groups compared with values from healthy, postmenopausal women. Specifically, the bone formation rate (BFR/BV and BFR/BS) was approximately 5 times lower in the ibandronate-treated (3 mg) group than in healthy, postmenopausal women. Histomorphometric analysis of transiliac bone biopsies demonstrated normal micro-structure of newly formed bone with normal mineralization and reduced remodeling after oral or IV ibandronate.

A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate.

Oral daily and weekly bisphosphonates represent the current mainstay of treatment for postmenopausal osteoporosis (PMO). However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long term. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Such regimens require high potency agents, which can be given at low effective doses and that also have good tolerability. Ibandronate is a potent, nitrogen-containing bisphosphonate with proven efficacy when given intermittently to estrogen-depleted beagle dogs, rats and cynomolgus monkeys. Clinically, a pivotal prospective study has established that oral ibandronate has significant vertebral fracture efficacy in PMO, whether given daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months; extended between-dose interval>2 months). Both oral regimens were well tolerated, which is noteworthy as patients with a history of gastrointestinal (GI) disturbance were not specifically excluded. As a result of these findings, a large, multinational, randomized, double-blind study (Monthly Oral iBandronate In LadiEs: MOBILE) is currently exploring the non-inferiority of once-monthly oral ibandronate (100 or 150 mg) to the oral daily ibandronate (2.5 mg) regimen with proven anti-fracture efficacy, in terms of lumbar spine bone mineral density (BMD) change. As with the trials investigating the weekly administration of other bisphosphonates, vertebral fracture efficacy will be inferred if the study demonstrates the non-inferiority of once-monthly ibandronate to the proven oral daily regimen in terms of spinal BMD change. The availability of this once-monthly ibandronate regimen is expected to offer benefits in terms of convenience (by having to follow dosing recommendations once a month vs. once daily or weekly) and potentially tolerability (by reducing the potential for upper GI irritation that can result from frequent, repeated exposure). Greater convenience and tolerability may enhance the therapy adherence and, hence, improve long-term therapeutic outcomes in PMO.